Blockage of the NLRP3 inflammasome by MCC950 improves anti-tumor immune responses in head and neck squamous cell carcinoma

Abstract

The NLRP3 inflammasome is a critical innate immune pathway responsible for producing active interleukin (IL)-1β, which is associated with tumor development and immunity. However, the mechanisms regulating the inflammatory microenvironment, tumorigenesis and tumor immunity are unclear. Herein, we show that the NLRP3 inflammasome was over-expressed in human HNSCC tissues and that the IL-1β concentration was increased in the peripheral blood of HNSCC patients. Additionally, elevated NLRP3 inflammasome levels were detected in tumor tissues of Tgfbr1/Pten 2cKO HNSCC mice, and elevated IL-1β levels were detected in the peripheral blood serum, spleen, draining lymph nodes and tumor tissues. Blocking NLRP3 inflammasome activation using MCC950 remarkably reduced IL-1β production in an HNSCC mouse model and reduced the numbers of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). Moreover, inhibiting NLRP3 inflammasome activation increased the numbers of CD4 and CD8 T cells in HNSCC mice. Notably, the numbers of exhausted PD-1 and Tim3 T cells were significantly reduced. A human HNSCC tissue microarray showed that NLRP3 inflammasome expression was correlated with the expression of CD8 and CD4, the Treg marker Foxp3, the MDSC markers CD11b and CD33, and the TAM markers CD68 and CD163, PD-1 and Tim3. Overall, our results demonstrate that the NLRP3 inflammasome/IL-1β pathway promotes tumorigenesis in HNSCC and inactivation of this pathway delays tumor growth, accompanied by decreased immunosuppressive cell accumulation and an increased number of effector T cells. Thus, inhibition of the tumor microenvironment through the NLRP3 inflammasome/IL-1β pathway may provide a novel approach for HNSCC therapy.

Interleukin-1 Beta—A Friend or Foe in Malignancies?

“…In agreement, in a mouse breast cancer model inhibition of NLRP3 effectively reduced the tumor-resident population of MDCS [288] and TAM [232]. Similarly, in a HNSCC mouse model, a reduction of MDSC, Treg and TAM frequencies was achieved by blocking NLRP3 inflammasome activation using the specific inhibitor MCC950 [226]. Comparable effects were observed in murine and human breast cancer models when applying Anakinra.…”

“…In addition, Treg and carcinoma-associated fibroblasts (CAF) contribute to the immunosuppressive milieu [222,223,224,225]. In a head and neck squamous cell carcinoma (HNSCC) mouse model inflammasome activation and thereby IL-1β upregulation was shown to cause an insufficient anti-tumor reactivity via the immunosuppressive network of MDSC, TAM and Treg [226]. MDSC and Treg have also been illustrated to be key negative regulators of the immune system in melanoma patients [227,228,229].…”

NLRP3 inflammasome: A likely target for the treatment of allergic diseases

“…Several specific inhibitors, such as MCC950, CY‐09, arglabin, and glyburide, have been recently developed or identified to target NLRP3 inflammasome inhibition . The application of these specific NLRP3 inflammasome inhibitors has demonstrated therapeutic effects in various inflammatory disease mouse models, including models of myocardial infarction, fulminant hepatitis, steatohepatitis, lupus nephritis, atherosclerosis, Alzheimer's disease, brain injury, inflammatory bowel diseases, acute colitis, and carcinoma In allergic diseases, the application of MCC950 reduces skin and airway inflammation in mouse models of allergic dermatitis and asthma . More recently, 2 studies have shown that the targeted inhibition of NLRP3 inflammasomes with a specific inhibitor decreased IL‐1β and TH2 cytokines and inhibited HDM‐induced AHR and steroid‐resistant asthma in a mouse model .…”

NLRP3 Inflammasome Activation in Cancer: A Double-Edged Sword

“…However, these cells secrete biologically active IL-1β in an autonomous way without the presence of exogenous stimuli at late stages of the disease ( 54 ). In HNSCC, NLRP3 inflammasome is found upregulated in carcinoma tissues and associated with carcinogenesis and cancer stem cells (CSCs) self-renewal activation ( 46 – 48 ). Also, NLRP3 signaling seems to drive immunosuppression in pancreatic carcinoma, by promoting tolerogenic T cell differentiation and adaptive immune suppression via IL-10 ( 56 ).…”